We have demonstrated that frequent relapse of follicular lymphoma, the major obstacle to cure, is a consequence of clonal expansion of daughter cells derived from a common stem cell. Thus, despite the "clinical" remission achieved by therapy in most patients, residual lymphoma cells must persist. To detect occult lymphoma, we have specifically amplified the joined bc1-2/JH DNA sequences created by the t(14;18) translocation seen in nearly all follicular lymphomas. Using multiple rounds of primer-directed DNA polymerization (Polymerase chain reaction, PCR), we can detect 1 copy of bc1-2/JH, which is 4 orders of magnitude more sensitive than flow cytometry or Southern blot restriction analysis. Genomic DNA sequence analysis of four lymphomas confirmed that the size of the amplified fragment serves as a unique tumor marker. Direct application to clinical samples has demonstrated lymphoma cells which were otherwise undetectable. Human T cell neoplasms are nearly always clonal and show coincident rearrangement of their T cell receptor beta and gamma genes. The T cell receptor delta gene is deleted from both chromosomes in most mature T cell neoplasms but is retained and frequently rearranged in precursor T and B cell neoplasms (ALL). Our findings demonstrate an ordered hierarchy whereby human delta gene assembly precedes rearrangement of either the beta or gamma genes and involves an extremely narrow pattern of V-delta usage. Many of the additional rearrangements we have observed in the delta locus may be due to chromosomal translocation in this region (14qll) which is frequently translocated in T cell neoplasms.